EP1854480A2 - Behandlung von LFA-1-assoziierten Krankheiten durch gesteigerte Dosen von LFA-1-Antagonist - Google Patents

Behandlung von LFA-1-assoziierten Krankheiten durch gesteigerte Dosen von LFA-1-Antagonist Download PDF

Info

Publication number
EP1854480A2
EP1854480A2 EP07012360A EP07012360A EP1854480A2 EP 1854480 A2 EP1854480 A2 EP 1854480A2 EP 07012360 A EP07012360 A EP 07012360A EP 07012360 A EP07012360 A EP 07012360A EP 1854480 A2 EP1854480 A2 EP 1854480A2
Authority
EP
European Patent Office
Prior art keywords
dose
antibody
compound
therapeutic
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07012360A
Other languages
English (en)
French (fr)
Other versions
EP1854480A3 (de
Inventor
Russell L. Dedrick
Marvin R. Garavoy
Susan M. Kramer
Karen Starko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Xoma Technology Ltd USA
Original Assignee
Genentech Inc
Xoma Technology Ltd USA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genentech Inc, Xoma Technology Ltd USA filed Critical Genentech Inc
Publication of EP1854480A2 publication Critical patent/EP1854480A2/de
Publication of EP1854480A3 publication Critical patent/EP1854480A3/de
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2845—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • the invention relates to methods of treating mammals, for example humans, to reduce the occurrence of undesired administration reactions, to treat an LFA-1 mediated disease, to condition a mammal to tolerate high doses of a therapeutic compound and to down modulate a cell surface receptor.
  • Antibodies are one type of polypeptide compound for which there are frequently adverse events upon administration which limit the dose of the compound that can be administered.
  • One compound associated with adverse side effects is the murine monoclonal antibody OKT3.
  • OKT3 binds to the CD3 protein complex that is associated with the T cell receptor (TCR) found on the surface of all T lymphocytes.
  • TCR T cell receptor
  • Administration of OKT3 to humans rapidly reduces the number of circulating T cells (e.g. OKT3 is a cell depleting compound) and reduces the amount of cell surface TCR found on those T cells that remain ( Cosimi, et al., 1981 N Engl J Med, 305(6), 308-314 ).
  • OKT3 The immunosuppressive effects of OKT3 have been therapeutically useful in the treatment of renal transplant rejection ( Goldstein & Group, 1985 M Engl J Med, 313(6), 337-342 ).
  • administration of OKT3 induces a number of adverse side effects, including fever, chills, nausea, vomiting and tightness of chest.
  • side effects are believed to be caused by cytokine release from T cells due to OKT3-induced activation ( Abramowicz, et al., 1989 Transplantation, 47(4), 606-608 ) and complement activation ( Raasveld, et al., 1993 Kidney International, 43 1140-1149 ).
  • a standard 5 mg dose of OKT3 administered as a 2 hour infusion instead of the usual bolus injection was better tolerated and reduced complement activation, but not the cytokine release ( ten Berge, Buysmann, van Diepen, Surachno, &hack. 1996 Transplant Proc. 28 (6), 3217-3220 ).
  • the adverse events induced by OKT3 are most significant after the first dose. While the initial dose (typically 5 mg) induces cytokine release and activates complement, it also eliminates the target T cells. With fewer T cells and reduced TCR density on those that do remain, subsequent doses of OKT3 induce less cytokine release ( Chatenoud, et al., 1989 N Engl J Med, 320 (21), 1420-1421 ).
  • Adverse events have also been associated with the initial administration of monoclonal antibodies directed to other cell surface molecules.
  • a humanized anti-CD4 monoclonal antibody induced fever, chills, hypotension and chest tightness when given intravenously to psoriasis and rheumatoid arthritis patients ( Isaacs, et al., 1997 Clin Exp Immunol, 110, 158-166 ).
  • This treatment down-modulated expression of CD4 and caused a reduction in the number of circulating CD4-positive T cells, and but was not completely depleting.
  • Bispecific antibodies that interact with the CD64 molecule, a receptor for the constant region of immunoglobulin (Fc gamma RI), and tumor associated molecules (epidermal growth factor receptor MDX-447, or HER2/neu MDX-H210) were shown to cause flu-like symptoms such as fever and chills after the first dose ( Curnow, 1997, Cancer Immunol lmmunother, 45, 210-215 ). Similar to the effect of OKT3 on T cells, these antibodies caused a decrease in the number of circulating monocytes, which express CD64, and stimulated increases in plasma cytokines. A single dose of another monoclonal antibody directed to CD64 (MDX-33) down-modulated the expression of CD64 on monocytes and also caused chills, low-grade fever, headache and muscle aches.
  • Fc gamma RI tumor associated molecules
  • T-lymphocytes with antigen-presenting cells (APCs) is one of the initial steps in the activation of an immunological response to what is perceived by the immune system to be a foreign antigen.
  • APCs antigen-presenting cells
  • Interfering with the binding of any of these ligand pairs may decrease, inhibit, or discontinue the T-cell responses ( de Fourgerolles et al., 1994, J. Exp. Med., 179:619-29 ; Dustin, ML et al, 1986, J Immunol, 137:245-54 ).
  • LFA-1 (consisting of CD 11a and CD18 subunits) interaction with ICAM is necessary for T-cell killing, T-helper and B-cell responses, natural killing, and antibody-dependent cytotoxicity.
  • LFA-1/ICAM interactions are involved in adherence of leukocytes to endothelial cells, fibroblasts, and epithelial cells, facilitating the migration of leukocytes from the vasculature to the sites of inflammation ( Collins, T., 1995, Science and Medicine, 28-37 ; Dustin, ML. et al., 1991, Annual Rev Immunology, 9:27-66 ).
  • One object of the present invention is to provide an improved method of administering a therapeutic compound. This and other objects which will become apparent from the following description of enabling embodiments have been achieved by the method of the invention.
  • One aspect of the invention is a method for reducing the occurrence of fever, headache, nausea and/or vomiting associated with administration of a therapeutic compound to a mammal in need thereof by administering to the mammal a first conditioning dose of a non-target cell depleting compound which binds to a cell surface receptor on a target mammalian cell; and then administering at least a second therapeutic dose of the compound, wherein the second dose is higher than the first dose.
  • a further aspect of the invention is a method for treating an LFA-1 mediated disorder by administering to a mammal in need thereof a first conditioning dose of a compound which binds to lymphocyte surface receptor LFA-1; and then administering at least a second therapeutic dose of the compound, wherein the second dose is higher than the first dose.
  • LFA-1 mediated disorders contemplated include psoriasis, asthma, rheumatoid arthritis, multiple sclerosis and transplant rejection.
  • the graft or transplant is a renal transplant.
  • a further aspect of the invention is a method for conditioning a mammal to tolerate high doses of a therapeutic compound by administering to the mammal a first conditioning dose of a non-target cell depleting compound which binds to a cell surface receptor on a target mammalian cell ; and then administering at least a second therapeutic dose of the compound, wherein the second dose is higher than the first dose.
  • Another aspect of the invention is a method for down modulating a cell surface receptor in a mammalian cell population by contacting a target mammalian cell displaying a receptor molecule on the surface thereof with a first dose of a ligand which binds to the receptor molecule and does not deplete the mammalian cell population; and then further contacting the mammalian DCi population with at least a second dose of the ligand, wherein the second dose is higher than the first dose.
  • the therapeutic compound comprises a polypeptide which binds to an extracellular domain of the receptor molecule.
  • a preferred polypeptide is an antibody or a fragment thereof.
  • the target mammalian cell is a lymphocyte such as a T lymphocyte.
  • Intravenous or subcutaneous mode of administration of the therapeutic compound is contemplated.
  • administration is not more than once per week.
  • the methods further comprise administering a third therapeutic dose, wherein the third dose is higher than the second dose.
  • the administration of a fourth therapeutic dose is higher than or equal to the third dose.
  • composition comprising an anti-CD11a antibody or fragment thereof, and a pharmaceutical carrier, for use as an active pharmaceutical agent for treating an LFA-1 mediated disorder, wherein the antibody is a non-target cell-depleting antibody and wherein the composition is administered to the mammal as a first conditioning dose followed by a second therapeutic dose, wherein the second therapeutic dose is higher than the first dose.
  • a compound which binds to the lymphocyte surface receptor LFA- in the preparation of a medicament for the treatment of an LFA-1 I mediated disorder which treatment comprises administering to the mammal, a first conditioning dose of the compound followed by a second therapeutic dose of the compound wherein the second therapeutic dose is higher than the first dose.
  • antibody is used in the broadest sense and specifically covers single monoclonal antibodies, antibody compositions with polyepitopic specificity, as well as antibody fragments (e.g., Fab, F(ab') 2 , scFv and Fv), so long as they exhibit the desired biological activity.
  • the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e ., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler & Milstein, Nature, 256:495 (1975 ), or may be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567 (Cabilly et al .)).
  • the monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity, e.g. binding to a cell surface receptor ( U.S. Patent No. 4,816,567 (Cabilly et al. ); and Morrison et al., Proc. Natl. Acad Sci. USA, 81:6851-6855 (1984) ).
  • chimeric antibodies immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or sub
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementarity determining region
  • humanized antibody may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and optimize antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Single-chain Fv or “sFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the sFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (V H ) connected to a light chain variable domain (V L ) in the same polypeptide chain (V H and V L ).
  • V H heavy chain variable domain
  • V L light chain variable domain
  • linear antibodies when used throughout this application refers to the antibodies described in Zapata et al. Protein Eng. 8(10):1057-1062 (1995) . Briefly, these antibodies comprise a pair of tandem Fd segments (V H -C H 1-V H -C H 1) which form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific.
  • a “variant” antibody refers herein to a molecule which differs in amino acid sequence from a "parent” antibody amino acid sequence by virtue of addition, deletion and/or substitution of one or more amino acid residue(s) in the parent antibody sequence.
  • the variant comprises one or more amino acid substitution(s) in one or more hypervariable region(s) of the parent antibody.
  • the variant may comprise at least one, e.g. from about one to about ten, and preferably from about two to about five, substitutions in one or more hypervariable regions of the parent antibody.
  • the variant will have an amino acid sequence having at least 75% amino acid sequence identity with the parent antibody heavy or light chain variable domain sequences, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%.
  • Identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the parent antibody residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. None of N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity or homology.
  • the variant retains the ability to bind the receptor and preferably has properties which are superior to those of the parent antibody.
  • the variant may have a stronger binding affinity, enhanced ability to activate the receptor, etc.
  • a Fab form of the variant to a Fab form of the parent antibody or a full length form of the variant to a full length form of the parent antibody, for example, since it has been found that the format of the antibody impacts its activity in the biological activity assays disclosed herein.
  • the variant antibody of particular interest herein is one which displays at least about 10 fold, preferably at least about 20 fold, and most preferably at least about 50 fold, enhancement in biological activity when compared to the parent antibody.
  • down modulating a cell surface receptor means a process or method which reduces the number of molecules of the receptor on the surface of a cell type relative to the number of molecules of the receptor before the process or method was performed. For example, the administration of a therapeutic compound which binds to a cell surface receptor will down regulate the receptor if the number of receptor molecules on the surface of the cell is less after administration than before administration of the compound.
  • the number of cell surface receptor molecules can be measured histologically using known staining and counting methods.
  • a “conditioning dose” is a dose which attenuates or reduces the frequency or the severity of first dose adverse side effects associated with administration of a therapeutic compound.
  • the conditioning dose may be a therapeutic dose, a sub-therapeutic dose, a symptomatic dose or a sub-symptomatic dose.
  • a therapeutic dose is a dose which exhibits a therapeutic effect on the patient and a sub-therapeutic dose is a dose which dose not exhibit a therapeutic effect on the patient treated.
  • a symptomatic dose is a dose which induces at least one adverse effect on administration and a sub-symptomatic dose is a dose which does not induce an adverse effect.
  • cell surface receptor means any molecule displayed on the surface of a cell and available for binding by therapeutic compounds which contact the surface of the cell. Such a cell surface molecule is a "receptor" for the therapeutic compound.
  • Human leukocyte surface markers including but not limited to CD2, CD29, CD40, CD49a-d and CD58 may be cell surface receptors within the invention. Suitable cell surface receptors also include cell adhesion molecules such as the leukocyte integrins CD11a/CD18, CD11b/CD18, CD11c/CD18 and CD11d/CD18 which are heterodimeric surface receptor molecules.
  • a therapeutic compound may bind to either member of the heterodimeric pair.
  • the cell surface receptor may have an extracellular domain which available for binding to a therapeutic compound as well as transmembrane and intracellular domains.
  • Other examples of receptors include protein kinase receptors capable of intracellular signaling through tyrosine phosphorylation, etc.
  • non-target cell depleting compound or a compound or ligand which "does not deplete" a cell population means a compound which binds to a cell surface receptor molecule, but does not substantially reduce the number of cells in the cell population.
  • a non-depleting compound for example, will reduce the number of cells in a cell population by about 50% or less, preferably by about 30% or less, more preferably by about 20% or less, relative to the number of target cells in the cell population prior to contact or treatment with the compound.
  • LFA-1-mediated disorders refers to pathological states caused by cell adherence interactions involving the LFA-1 receptor on lymphocytes.
  • T cell inflammatory responses such as inflammatory skin diseases including psoriasis; responses associated with inflammatory bowel disease (such as Crohn's disease and ulcerative colitis); adult respiratory distress syndrome; dermatitis; meningitis; encephalitis; uveitic; allergic conditions such as eczema and asthma and other conditions involving infiltration of T cells and chronic inflammatory responses; skin hypersensitivity reactions (including poison ivy and poison oak); atherosclerosis; leukocyte adhesion deficiency; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes, and immune responses associated with delayed hypersensitivity
  • Treating" a disease, disorder, condition or cell population includes therapy and prophylactic treatment on an acute short term basis and on a chronic long-term basis.
  • mammal refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • mammal herein is human.
  • a "ligand” or a "compound” which binds to a receptor molecule on the surface of a cell may be any compound capable of binding to the receptor molecule.
  • the therapeutic compound may, for example, be a small organic molecule (preferably having a molecular weight of about 1000 g/mole or less) or a polypeptide.
  • Suitable polypeptide compounds or ligands can be prepared by methods known in the art, for example, by isolating peptides or proteins having high binding affinities for the surface molecule using phage display technology.
  • Phage display methods are disclosed, for example, in US 5,750,373 ; US 5,821,047 ; US 5,780,279 ; US 5,403,484 ; US 5,223,409 ; US 5,571,698 ; etc.
  • large libraries of peptides or proteins displayed on the surface of phage are produced and screened or panned to select those members of the library which bind strongly to a target molecule which is generally immobilized on a solid support.
  • These methods may be used to select peptides or proteins which bind to a cell surface receptor by screening a phage display library using the cell surface receptor as the target molecule. Repeated rounds of selection and separation of the binders having high binding affinity produces polypeptide compounds capable of binding to the cell surface receptor.
  • the polypeptide may be an antibody or an antibody fragment.
  • a “therapeutic” compound is any compound which is used in treating a mammal.
  • a compound which binds to lymphocyte surface receptor LFA-1 generally refers to any compound capable of binding to either component of LFA-1.
  • the compound may be a protein which recognizes and binds to LFA-1, for example a binding protein, an antibody directed against either CD11a or CD18 or both, but also includes ICAM-1, soluble forms of ICAM-1 (e.g., the ICAM-1 extracellular domain, alone or fused to an immunoglobulin sequence), antibodies to ICAM-1, and fragments thereof, or other molecules capable of inhibiting the interaction of LFA-1 and ICAM-1.
  • anti-LFA-1 antibody or "anti-LFA-1 MAb” refers to an antibody directed against either CD11a or CD18 or both.
  • the anti-CD11a antibodies include, e.g., MHM24 [ Hildreth et al.. Eur. J. Immunol., 13:202-208 (1983 )], R3.1 (IgGl) [R. Rothlein, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT], 25-3 (or 25.3), an IgGl available from Immunotech, France [ Olive et al., in Feldmann, ed., Human T cell Clones. A new Approach to Immune Regulation, Clifton, NJ, Humana, 1986 p.
  • anti-CD18 antibodies examples include MHM23 [Hildreth et al., supra ], M1812 (IgG2a) [ Sanches-Madrid et al., J. Exp. Med. 158: 586 (1983 )], H52 [ Fekete et al., J. Clin. Lab Immunol., 31: 145-149 (1990 )], Mas191c [Vermot Desroches et al., supra ], IOT18 [Vermot Desroches et al., supra ] , 60.3 [ Taylor et al.. Clin. Exp. Immunol., 71: 324-328 (1988 )], and 60.1 [ Campana et al.. Eur. J. Immunol., 16: 537-542 (1986 )].
  • LFA-1 binding molecules including antibodies
  • WO 91/18011 published 11/28/91
  • WO 91/16928 published 11/14/91
  • WO 91/16927 published 11/14/91
  • Can. Pat. Appln. 2,008,368 published 6/13/91
  • WO 90/15076 published 12/13/90
  • WO 90/10652 published 9/20/90
  • EP 387,668 published 9/19/90
  • EP 379,904 published 8/1/90.
  • EP 346,078 published 12/13/89
  • U.S. Pat. No. 5,071,964 U.S. Pat. No. 5,002,869
  • Australian Pat. Appln. 8815518 published 11/10/88
  • EP 289,949 published 11/9/88
  • EP 303,692 published 2/22/89.
  • the antibody is appropriately from any source, including chicken and mammalian such as rodent, goat, primate, and human.
  • the antibody is from the same species as the species to be treated, and more preferably the antibody is human or humanized and the host is human.
  • the antibody can be a polyclonal or monoclonal antibody, preferably it is a monoclonal antibody, which can be prepared by conventional technology.
  • the antibody is an IgG-1 , -2, -3, or -4, IgE, IgA, IgM, IgD, or an intraclass chimera in which Fv or a CDR from one class is substituted into another class.
  • the antibody may have an Fc domain capable of an effector function or may not be capable of binding complement or participating in ADCC.
  • a dosing schedule in which a first conditioning dose of a non-target cell depleting compound which binds to a cell surface receptor on a target mammalian cell is followed by a second higher dose of the compound, is effective in conditioning a mammal to tolerate increasing or higher doses of the therapeutic compound.
  • This dosing schedule allows one to reduce the occurrence of adverse effects which arise from the initial administration and subsequent administrations of the therapeutic compound, that is, the method of the invention reduces the first dose adverse effects of administration and condition the mammal to further higher doses.
  • the method of the present invention allows one to increase subsequent doses and obtain the therapeutic benefit of higher doses of the therapeutic compounds, while, at the same time, minimizing the occurrence of adverse side effects.
  • the therapeutic compound which is administered using the dosing schedule of the present invention is a non-target cell depleting compound which binds to a cell surface receptor on the target cell.
  • a non-target cell depleting compound which binds to a cell surface receptor on the target cell.
  • Such a compound does not substantially reduce the number of cells in the cell population.
  • the target cell is a lymphocyte
  • administration of a non-lymphocyte cell depleting compound according to the dosing schedule of the present invention will result in binding of the compound to a lymphocyte cell surface receptor, but will not result in a decrease in the number of circulating lymphocytes over the course of administration of the therapeutic compound.
  • administration of the therapeutic compound will, in some cases, result in increases in the number of target cells in the cell population, however, and such an effect is to be considered within the scope of the present invention.
  • the non-target cell depleting compound which is administered according to the method of the invention may be any non-depleting therapeutic compound which is capable of binding to a cell surface receptor.
  • Many therapeutic compounds are well known to exert a therapeutic effect by binding to a selective cell surface marker or receptor. These known therapeutic compounds will be apparent to one having ordinary skill in the art and may be used in the method of the present invention.
  • Suitable therapeutic compounds include non-peptidic organic compounds, preferably having a molecular weight less than about 1,000 g/mol, more preferably less than about 600 g/mol; peptide therapeutic compounds, generally containing 8 to about 200, preferably about 15 to about 150, more preferably about 20 to about 100 amino acid residues; and protein therapeutic compounds, generally having secondary, tertiary and possibly quaternary structure.
  • Suitable peptides compounds can be prepared by known solid-phase synthesis or recombinant DNA technology which are well known in the art.
  • a particularly preferred method of selecting a non-depleting peptide compound is through the use of phage display technology.
  • libraries of peptides or proteins are prepared in which one or more copies of individual peptides or proteins are displayed on the surface of a bacteriophage particle.
  • DNA encoding the particular peptide or protein is within the phage particle.
  • the surface-displayed peptides or proteins are available for interaction and binding to target molecules which are generally immobilized on a solid support such as a 96-well plate or chromatography column support material. Binding and/or interaction of the display peptide or protein with a target molecule under selected screening conditions allows one to select members of the library which bind or react with the target molecule under the selected conditions.
  • peptides which bind under particular pH or ionic conditions may be selected.
  • a target cell population can be immobilized on a solid surface using known techniques and the peptide or protein phage library can be panned against the immobilized cells to select peptides or proteins which bind to cell surface receptors on the target cell population.
  • Phage display techniques are disclosed, for example, in U.S. 5,750,373 ; U.S. 5, 821,047 ; U.S. 5,780,279 ; U.S. 5,403,484 ; U.S. 5,223,407 ; U.S. 5,571,698 ; and others.
  • One category of preferred polypeptide non-depleting compounds are compounds containing an antibody or a fragment thereof which immunologically recognize and bind to cell surface receptors.
  • Methods of preparing antibodies to specific cell surface receptors are well known in the art and have been practiced for many years.
  • Suitable antibodies may be prepared using conventional hybridoma technology or by recombinant DNA methods.
  • Preferred antibodies are humanized forms of non-human antibodies.
  • antibodies may be prepared from antibody phage libraries using methods described, for example, in US 5.565,332 ; U.S. 5.837,242 : U.S. 5,858,657 ; U.S. 5,871907 ; U.S. 5,872,215 ; U.S. 5,733,743 , and others.
  • Suitable compounds include full-length antibodies as well as antibody fragments such as Fv, Fab, Fab' and F(ab') 2 fragments which can be prepared by reformatting the full length antibodies using known methods.
  • Additional preferred polypeptide therapeutic compounds are immunoadhesin molecules also known as hybrid immunoglobulins. These polypeptides are useful as cell adhesion molecules and ligands and also useful in therapeutic or diagnostic compositions and methods.
  • An immunoadhesin typically contains an amino acid sequence of a ligand binding partner protein fused at its C-terminus to the N-terminus of an immunoglobulin constant region sequence.
  • a suitable immunoadhesin may contain the extracellular domain of a leukocyte integrin molecule, e.g. LFA-1, LFA-2, LFA-3, MAC-1, p150,95, aDb2, etc., fused to the hinge and CH2 and/or CH3 sequences of the a human IgG constant region.
  • a first conditioning dose of a non-target cell-depleting compound which binds to a cell surface receptor on a target mammalian cell followed by a therapeutic dose.
  • therapeutic in this context means that the compounds binds to the surface of the target cell and produce a change in the symptoms or conditions associated with the disease or condition which is being treated. It is sufficient that a therapeutic dose produce an incremental change in the symptoms or conditions associated with the disease; a cure or complete remission of symptoms is not required.
  • One having ordinary skill in this art can easily determine whether a dose is therapeutic by establishing criteria for measuring changes in symptoms or conditions of the disease being treated and then monitoring changes in these criteria according to known methods.
  • the method of the invention may be used to treat psoriasis where therapeutic effect is determined by a physician's global assessment (PGA) of the patient and by Psoriases Area and Severity Index (PASI) scores. A decrease in PASI score indicates a therapeutic effect.
  • Psoriatic disease activity can also be determined based on Overall Lesion Severity (OLS) scale, percentage of total body surface area (BSA) affected by psoriasis, and psoriasis plaque thickness.
  • one indicator of therapeutic effect is a decrease in nonspecific airway hyperresponsiveness to methacholine challenges (basal and post-allergen; see Examples), upon treatment by the method of the invention.
  • Airway hyperresponsiveness can be measured by FEV 1 (volume of air that can be forced from the lungs in 1 second).
  • FEV 1 volume of air that can be forced from the lungs in 1 second.
  • therapeutic effectiveness can be measured, e.g., by the incidence of acute graft rejection, by graft function, and length of graft survival, as described in the Examples.
  • Other indicators of therapeutic effect will be readily apparent to one having ordinary skill in the art and may be used to establish efficacy of the dose.
  • the first dose serves to condition the mammal to tolerate the higher second therapeutic dose. In this way, the mammal is able to tolerate higher doses of the therapeutic compound than could be administered initially.
  • additional doses which may be administered after the second dose. For example, an additional, third dose which is higher than or equal to the second dose and an additional fourth dose which is higher than or equal to the second or third dose are contemplated within the method of present invention.
  • the first dose may be repeated one or more times before the second higher dose is administered.
  • the first dose may be administered, for example, one, two or three times, most preferably only one time before the second higher dose is administered.
  • the doses may be administered according to any time schedule which is appropriate for treatment of the disease or condition.
  • the dosages may be administered on a daily, weekly, biweekly or monthly basis in order to achieve the desired therapeutic effect and reduction in adverse effects.
  • the dosages can be administered before, during or after the development of the disorder.
  • the initial conditioning dose may be administered before, during or after transplantation has occurred.
  • the specific time schedule can be readily determined by a physician having ordinary skill in administering the therapeutic compound by routine adjustments-of the dosing schedule within the method of the present invention.
  • the time of administration of the first and second dosages as well as subsequent dosages will be adjusted to minimize adverse effects while maintaining a maximum therapeutic effect.
  • the occurrence of adverse effects can be monitored by routine patient interviews and adjusted to minimize the occurrence of side effects, in particular, fever, headache, nausea and/or vomiting by adjusting the time of the dosing. Any dosing time is to be considered to be within the scope of the present invention so long as the first conditioning dose of the non-depleting compound is administered followed by a second higher dose of the compound. For example, additional doses may be on a daily or weekly schedule followed by subsequent biweekly or monthly doses.
  • the dosage amount will depend on the specific disease or condition which is treated and can be readily determined using known dosage adjustment techniques by a physician having ordinary skill in treatment of the disease or condition.
  • the dosage amount will generally lie with an established therapeutic window for the therapeutic compound which will provide a therapeutic effect while minimizing additional morbidity and mortality.
  • therapeutic compounds will be administered in a dosage ranging from 0.001 mg/kg to about 100 mg/kg per dose, preferably 0.1-20 mg/kg.
  • the preferred dose of about 0.1-20mg/kg is particularly useful for non-cell depleting compounds containing antibodies or fragments thereof.
  • the therapeutic compound used in the method of this invention is formulated by mixing it at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed.
  • the pH of the formulation depends mainly on the particular use and the concentration of antagonist, but preferably ranges anywhere from about 3 to about 8.
  • Formulation in an acetate buffer at pH 5 is a suitable embodiment.
  • the therapeutic compound is an anti-LFA-1 antibody (such as hu1124)
  • a suitable embodiment is a formulation at pH 6.0.
  • the therapeutic compound e.g. an anti-LFA-1 antibody
  • the therapeutic compound for use herein is preferably sterile. Sterility can be readily accomplished by sterile filtration through (0.2 micron) membranes. Preferably, therapeutic peptides and proteins are stored as aqueous solutions, although lyophilized formulations for reconstitution are acceptable.
  • the therapeutic compound may be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the time scheduling of administration, and other factors known to medical practitioners.
  • the "therapeutically effective amount" of the therapeutic compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the disease, for example an LFA-1-mediated disorder, including treating rheumatoid arthritis, psoriasis, multiple sclerosis, asthma, or prolonging survival of a transplanted graft. Such amount is preferably below the amount that is toxic to the host or renders the host significantly more susceptible to infections.
  • the therapeutic compound may be administered by any suitable means, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, and intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the-dosing is given by injections, most preferably intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • a method of down-modulating a cell surface receptor in a cell population in a mammal by contacting a target mammalian cell displaying a receptor molecule on the surface thereof with a first dose of a ligand which binds to the receptor molecule and does not deplete the mammalian cell population; and then further contacting the mammalian cell population with a second dose of the ligand, wherein the second dose is higher than the first dose. Binding of the ligand to the cell surface receptor reduces the number of receptors on the surface of the cell even though the numbers of cells are not substantially reduced. This reduction in surface receptors is associated with reduced side effects such as reduced fever, headache, nausea and/or vomiting.
  • the non-cell depleting compound or ligand used in this method may be same as described above, and may be provided to the mammal in the same manner of administration, using the same dosing schedule and in the same dosage amounts as described above.
  • Another aspect of the invention is the treatment of an LFA- l mediated disorder by administering to a mammal, preferably a human patient, in need of such a treatment a first conditioning dose of a compound which binds to lymphocyte surface receptor LFA-1; and administering a second therapeutic dose of the compound, where the second dose is higher than the first dose.
  • This aspect of the invention is different than conventional dosing methods for the treatment of such diseases which generally treat with regularly spaced, even doses of a therapeutic compound.
  • the immunoadhesin LFA-3TIP which is a recombinant dimeric protein consisting of the first extracellular domain of human LFA-3 fused to the hinge and CH2 and CH3 human IgG regions, has been administered in equal weekly doses of 0.005mg/kg, 0.025mg.kg, 0.050mg/kg or 0.075mg/kg.
  • the method of the invention provides a first conditioning dose and then a second therapeutic higher dose.
  • This method of dose scheduling conditions the patient to tolerate higher doses of the therapeutic compound than would be tolerated by the patient, particularly when there are adverse effects on the patients due to administration of the therapeutic compound.
  • the low first dose of the method of the invention is useful for reducing the fever, headache, nausea, vomiting, etc. which often accompany an initial administration of a drug compound. However, it is possible to give a low first dose, within the scope of the invention, to patients who do not experience adverse effects on first administration.
  • the first dose conditions the patient to receive a second higher dose with a reduction in adverse effects which may be observed with higher doses of therapeutic compounds.
  • the dosage amount increases, the number of adverse effects also increases.
  • the method of the invention allows administration of larger therapeutic doses more quickly and with fewer adverse effects. This improves the effectiveness of the therapy since the patient is able to tolerate larger doses and for a longer time since there are fewer unpleasant side effects.
  • any compound which binds to a lymphocyte surface receptor LFA-1 and reduces the severity of symptoms or conditions associated with an LFA-1 mediated disease may be used in this embodiment of the invention.
  • Preferred compounds are peptide or protein compounds, more preferably such compounds which are or which contain an antibody or fragment thereof or which are fusions to an antibody fragment such as an immunoadhesin.
  • Particularly preferred compounds are anti-CD 11a antibodies or compounds containing fragments thereof.
  • the dosage amount will depend on the specific LFA-1 mediated disease which is treated and can be readily determined using known dosage adjustment techniques by a physician having ordinary skill in treatment of these diseases.
  • the dosage amount will generally lie within an established therapeutic window for the therapeutic compound which will provide a therapeutic effect while minimizing additional morbidity and mortality.
  • therapeutic compounds will be administered in a dosage ranging from 0.001 mg/kg to about 100 mg/kg per dose, preferably 0.1-20 mg/kg.
  • the preferred dose of about is particularly useful for compounds containing antibodies or fragments thereof.
  • the therapeutic compound for treatment of an LFA-1 mediated disease may be administered by any suitable means, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, and intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the dosing is given by injections, most preferably intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • the therapeutic compound for treatment of an LFA-1 mediated disease may be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Psoriasis is an inflammatory disease characterized by hyperproliferation of keratinocytes and accumulation of activated T cells in the epidermis and dermis of psoriatic lesions.
  • the upregulation of ICAM-1 on keratinocytes and its interaction with T-cell LFA-1 in lesional skin indicate that treatment with an anti-CD11a antibody might interfere with the disease process in psoriasis.
  • Allergic asthma is characterized by the cardinal features of airway inflammation, reversible airway obstruction, and hyperresponsiveness.
  • lymphocytes are believed to play a central role in the asthmatic inflammatory response to an inhaled allergen.
  • Chronic asthma symptoms may result from continual activation of lung lymphocytes in response to chronic exposure to perennial allergens (e.g., house dust mite, dog dander, or cat hair) or from sequential exposure to seasonal allergens to which the patient is reactive.
  • the patient with allergic asthma will experience an immediate response (the early asthmatic response or EAR);which is characterized by a fall in the volume of air that can be forced from the lungs in 1 second (FEV 1 ) over 0-2 hours. In most cases, this fall in FEV 1 is reversible by treatment with a ⁇ -agonist bronchodilator. Approximately 50% of these patients will go on to experience a second fall in FEV 1 (the late asthmatic response or LAR) 3-7 hours after the initial allergen exposure. LAR is associated with more pronounced airway inflammation and increased bronchial reactivity to nonspecific stimuli.
  • Airway hyperresponsiveness to the non-allergen-specific challenge of methacholine is another cardinal feature of asthma. Hyperresponsiveness of the airways in response to low levels of methacholine is recognized by a decrease in FEV 1 and may be exacerbated by exposure of the airways to allergen, viral infection, or physical irritants. Aerosolized allergen bronchial challenge, or bronchoprovocation, can be performed in the laboratory in patients with allergic asthma and is useful and relevant as a model for the study of anti-asthma medications ( Crescioli et al. 1991 Ann Allergy 66:245-51 ; Cockcroft et al., 1987, Am Rev Respir Dis 135:264-267 : Ward et al. 1993, Am Rev Respir Dis 147:518-523 .).
  • Interleukins IL-5. IL-3
  • granulocyte/macrophage colony stimulating factor are known to be important for eosinophil differentiation, maturation, adherence, activation, and degranulation.
  • cytokines are produced by T cells isolated from patients with asthma ( Walker et al., 1991, J. Immunol. 146:1829-35 ).
  • the T-cell products IL-4 and IL-13 are key mediators of inflammation, increasing IgE levels.
  • Activated T cells are increased in peripheral blood, bronchoalveolar lavage, and bronchial biopsy specimens from patients with asthma ( Azzawi et al.
  • Lymphocytes are the predominant cell type identified in morphometric studies of submucosal biopsies obtained from patients with asthma ( Djukanovic et al., 1992, Am Rev Respir Dis 145:669-74 ).
  • the method of the invention is exemplified by the treatment of psoriasis, asthma and kidney transplant rejection (LFA-1 mediated diseases) with a therapeutic compound (an antibody) which binds to a cell surface receptor (CD11a).
  • a therapeutic compound an antibody which binds to a cell surface receptor (CD11a).
  • CD11a a cell surface receptor
  • hu1124 is a known humanized anti-CD11a antibody [see WO 98/23761 (humanized MHM24(Fab)-8); Werther WA, et al., Humanization of an anti lymphocyte function-associated antigen (LFA)-1 monoclonal antibody and re-engineering of the humanized antibody for binding to rhesus LFA-1. J Immunol 1996; 157:4986-95 ).
  • hu 1124 is a humanized IgG1 version of a murine anti-CD 11a monoclonal antibody, MHM24, which recognizes human and chimpanzee CD11a.
  • Humanization of MHM24 was accomplished by grafting the murine complementarity determining regions (hypervariable region) into consensus human IgG1/ ⁇ heavy- and light-chain sequences.
  • H and L chain V sequences of hu1124 refer to GenBank accession no. P_W62013 and P_W62017, respectively; sequences are also shown in Figure 1 in Werther et al., 1996, and in Fig.1A and 1B in WO 98/23761 , incorporated herein by reference).
  • the study drug, hu 1124 was supplied as a single-use, clear, colorless, sterile, non-pyrogenic solution in a glass vial. Each vial contained 10 mL of solution at a concentration of 4 mg/mL in 10 mM sodium acetate pH 5.0, with 0.02% polysorbate 20, 0.1 % sodium acetate trihydrate, and 4% mannitol. No preservative was added to the solution. All study drug was stored at 2-8°C (35.6-46.4°F). The study drug was administered to subjects by continuous intravenous infusion over 90 minutes into a peripheral vein. The amount of drug to be given was based on subject weight and the dosage group to which the subject was assigned.
  • Thirty-nine subjects with moderate to severe plaque psoriasis were enrolled at eight study centers.
  • the subjects included Caucasian, Black, Asian and Hispanic subjects.
  • the subjects ranged in age from 26 to 73 years, with only one subject older than 70.
  • Subject weight ranged from 65 to 122 kg.
  • Baseline PASI scores ranged from 15 to 42, with an overall median of 23 for the 39 subjects in this study.
  • Each of the 39 subjects received multiple doses of hu1124. ranging from 0.1-1.0 mg/kg, administered by intravenous infusion.
  • the first-dose acute adverse events were primarily fever (reported by 17/39 or 44% of subjects), headache (reported by 7/39 or 18% of subjects), nausea (reported by 5/39 or 13% of subjects), and vomiting (2/39 or 5% of subjects).
  • Acute (within 48 hours after dosing) adverse events of fever, headache, or vomiting after the first dose were not reported in subjects who received 0.1 mg/kg every other week or every week.
  • the majority of acute adverse events were mild in severity. Importantly, the frequency of acute adverse events decreased with subsequent doses in each dose group.
  • the mean peak and trough plasma levels of hu1124 appeared to be dose dependent and increased as the dose level of study medication increased. No accumulation of hu1124 was observed in the lower dose groups and a small degree of accumulation was observed after the maximum doses were infused in the higher dose groups. A decrease in CD11a expression was observed within 2-4 hours after study medication administration in all dose groups, with full recovery noted before the next dose in the lower dose groups and within 7-10 days after the hu1124 levels decreased to below detection levels. In the two highest dose groups, hu1124 binding sites remained saturated during the course of treatment.
  • the tetanus antibody test results indicated that an established humoral antibody response, especially a second set IgG mediated antibody response, is able to persist in the presence of multiple doses of hu1124.
  • Antibody response was evaluated in 36 of 39 patients by double antigen sandwich ELISA. No human anti-hu1124 antibody response was detected out to Day 98 after multiple weekly doses.
  • Efficacy was based on the global assessment of improvement, PASI scores, and histological analysis of skin biopsies. Some clinical improvement ( ⁇ poor improvement) was observed in 76% (29/38) of the, subjects at Day 56. Of the subjects who received at least 0.3 mg/kg/wk, 64% (18/28) experienced clinical improvement of at least fair. Five subjects experienced an excellent improvement (i.e., 75-90% improvement from baseline), with higher rates of clinical improvement noted as the dose of study drug was escalated. Continuous improvement at Day 70 was observed in six subjects in the higher dose groups. Subjects infused with the higher doses of hu1124 had greater decreases in their PASI scores compared with subjects infused with the lower doses. Ten subjects had a 50% decrease in their PASI scores.
  • This study assessed the safety, pharmacokinetics and pharmacodynamics, and biological activity of hu1124 administered by subcutaneous injection in a single dose and in multiple doses to subjects with moderate to severe plaque psoriasis.
  • the study drug, hu1124 was the same as used in Example 1. It was supplied as single use vials containing 100 milligrams of sterile, pyrogen-free, lyophilized drug product which contains hu1124 antibody at a concentration of 100 mg/mL and 0.02 mmole L-histidine, and 0.96 mmole ⁇ , ⁇ - trehalose, pH 6.0 when reconstituted with 1.0 mL of sterile water for injection.
  • Subjects in Group A 2 received a single injection of 0.3 mg/kg of hu1124.
  • Subjects in Groups B through E (n 24) received eight weekly injections in doses ranging from 0.5-2.0 mg/kg of hu1124.
  • Adverse events were reported and assessed in a manner similar to Example 1. Acute adverse events included headache, fever, chills, myalgia, nausea, and vomiting. Any of these adverse events occurring within 48 hours from the time of injection with hu1124 were considered acute. Safety was assessed by pre- and post-treatment examinations (including vital sign measurements), clinical laboratory assessments (including blood chemistries, hematology, and urinalysis), by examination of reported adverse clinical events, and by a hearing assessment. Evaluation of efficacy was based on PGA levels of improvements, changes in PASI scores, and histological analysis of skin biopsies at Day 56.
  • the study population was defined as subjects who had a history of and/or were considered for systemic therapy for chronic moderate to severe plaque-type psoriasis (BSA > 15% and PASI > 12) which had been diagnosed for at least six months and had been stable for at least three months.
  • BSA chronic moderate to severe plaque-type psoriasis
  • PASI PASI
  • Psoriasis Area and Severity Index (PASI) scores decreased by an average of 10.9% in the single dose 0.3 mg/kg group, by 47.1% in the 0.5 mg/kg group, by 36.3% in the 0.5-1.0 mg/kg group, by 33.2% in the 0.7-1.5 mg/kg group and by 35.6%, in the 1.0-2.0 mg/kg group.
  • PASI Psoriasis Area and Severity Index
  • Group C had a final enrollment of 21 subjects and Group E had 24 subjects, adding to a total of 55 subjects enrolled at 10 study centers (Group A study was discontinued).
  • the data generated from the total pool of 55 subjects from the multiple dose groups showed the following results and observations. Substantial improvements in PGA and PASI. scores were observed by Day 56. Of the 55 subjects in the multiple-dose groups, 45% experienced Good or better improvements in PGA (defined as an improvement of ⁇ 50% of all clinical signs and symptoms of psoriasis compared to baseline) and 47% experienced at least a 50% decrease in PASI scores. Furthermore, 18% of these subjects experienced at least a 75% reduction in PASI scores by Day 56 and were categorized as treatment responders. Among the multiple dose groups, higher proportions of subjects in the 0.5-1.0 mg/kg and 1.0-2.0 mg/kg groups experienced Good or better improvement in PGA. Of note, one subject in the 1.0-2.0 mg/kg group experienced compete resolution of disease symptoms as assessed by PGA. Higher proportions of subjects in these two dose groups also experienced at least 50% reductions in PASI scores compared with subjects in the other dose groups.
  • two treatment groups receive multiple intravenous doses of hu1124 from 0.3 mg/kg to 1.0 mg/kg, for 12 weeks. Each hu1124 dose will be administered one time weekly over a period of 90 minutes. Three treatment groups receive multiple subcutaneous doses of hu1124 from 0.7 to 4.0 mg/kg, injected one time weekly for 12 weeks.
  • the study drug hu1124
  • a glass vial contains 10 mL of solution at a concentration of 4 mg/mL in 10 mM sodium acetate pH 5.0. with 0.02% polysorbate 20, 0.1% sodium acetate trihydrate, and 4% mannitol. No preservative is added to the solution. All study drug is stored at 2-8°C (35.6-46.4°F).
  • the study drug is supplied as single use vials containing 100 milligrams of sterile, pyrogen-free, lyophilized drug product which contains hu1124 antibody at a concentration of 100 mg/mL and 0.02 mmole L-histidine, and 0.96 mmole ⁇ , ⁇ - trehalose, pH 6.0 when reconstituted with 1.0 mL of sterile water for injection.
  • Safety is assessed by pre- and post-treatment examinations (including vital sign measurements), hearing assessments, clinical laboratory assessments (including blood chemistries, hematology, and urinalysis), antibody to hu1124 (HAHA), and by examination of reported adverse clinical events as in the previous examples.
  • Pharmacokinetics are assessed using various ex vivo immunologic assays. Biological activity is assessed by changes in PASI.
  • Subjects receive 12 weekly doses of anti-CD11a (hu1124) or placebo administered by SC injection, as outlined in the Table of dosing schedule immediately below.
  • the doses consist of an initial conditioning dose at a concentration of 0.7 mg/kg SC and weekly doses of 1.0 mg/kg administered SC or 2.0 mg/kg SC thereafter.
  • TABLE 4 Dosing Schedule Day 0 7 14 21 28 35 42 49 56 63 70 77 Low dose (mg/kg) 0.7 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 High dose (mg/kg) 0.7 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
  • Anti-CD11a (hu1124) is supplied as in the above Examples 2 and 3. When reconstituted with 1.0 mL of Sterile Water for Injection (SWFI), each vial contains hu1124 at a concentration of 100 mg/mL. as well as polysorbate 20. L-histidine hydrochloride, and ⁇ -trehalose, at pH of 6.0.
  • SWFI Sterile Water for Injection
  • FT Day 84 Primary efficacy determinations are made on FT Day 84, which is the end of the First Treatment (FT) period.
  • FT Day84 subjects are defined as responders, partial responders, or non-responders according to the following definitions: Responder: PASI has decreased ⁇ 75% from FT Day 0; Partial responder: PASI has decreased ⁇ 50% but ⁇ 75% from FT Day 0; Non-responder: PASI has decreased ⁇ 50% from FT Day 0.
  • This response to therapy determines whether subjects are assigned to the Observation (OB) or Extended Treatment (ET) period after completion of the FT Day 84 assessments.
  • Subjects defined as responders enter the Observation (OB) period and are followed either for 6 months or until relapse, whichever occurs first.
  • Relapse is defined as loss of 50% or more of the improvement in PASI achieved between FT Day 0 and FT Day 84 (see Section 4.5.3.a).
  • FT First Treatment
  • RT Treatment
  • Subjects who received placebo during the First Treatment (FT) period and qualify as responders receive anti-CD11a during the Treatment period.
  • subjects Despite re-randomization, subjects remain within the dose level group (low dose or high dose) assigned during the First Treatment (FT) period.
  • subjects receive a second course of treatment consisting of 12 weekly SC injections.
  • Subjects defined as partial responders or non-responders at the end of the First Treatment (FT) period are assigned to the Extended Treatment (ET) period. Subjects remain within the dose levels assigned in the First Treatment (FT) period. Subjects who had received anti-CD11a in the First Treatment (FT) period are re-randomized 2:1 to anti-CD11a or placebo, respectively. All subjects who received placebo in the First Treatment (FT) period are assigned to anti-CD11a within their dose level. ET Day 0 occurs on the same day as FT Day 84: hence the two courses of study drug treatment are continuous over a 24-week period.
  • UVB Ultraviolet B light
  • study drug (hu 1124 or placebo) is administered weekly by SC injection, for eight doses over 50 days (one dose per week). The first dose of study drug is administered on Day 0.
  • Subjects undergo allergen bronchial and methacholine challenges. Methacholine challenges, measuring nonspecific airway hyperresponsiveness (basal and post-allergen), are performed the day prior to a scheduled allergen challenge and ⁇ 24 hours following the start of allergen challenge.
  • the hu1124 antibody is supplied by Genentech as a sterile, pyrogen-free, lyophilized drug product in 10-mL glass vials.
  • SWFI Sterile Water for Injection
  • each vial contains hu1124 at a concentration of 100 mg/mL, 20 mmol of L-histidine, 240 mmol of ⁇ , ⁇ -trehalose, 0.04% polysorbate 20 (pH of 6.0).
  • the placebo formulation has the same product composition but does not contain hu1124.
  • Study drug is administered by SC injection in the forearm, thigh, or abdomen. The dosing regimen is shown in the table immediately below.
  • hu 1124 The safety and efficacy of hu 1124 are assessed by the incidence and severity of adverse events, laboratory tests, physical examinations including vital signs, spirometry, and serum antibody response to hu 1124 at baseline and during the treatment and follow-up periods. The incidence and magnitude of changes in hearing are assessed by audiograms. Efficacy measures include determining the change in LAR and EAR and allergen-induced increase in airway responsiveness. All subjects are followed for 28 days after dosing is complete.
  • Blood and urine samples are collected periodically for analysis of blood chemistries, hematology, and urinalysis. Specific parameters assessed are as follows: Chemistry: sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, total and direct bilirubin, albumin, ALT, AST, alkaline phosphatase, uric acid, total protein. Hematology: CBC with differential and platelet count. Urinalysis: complete urinalysis with microscopic examination. Serum antibodies to hu 1124. Serum samples for pharmacokinetic evaluations. Vital sign measurement consists of sitting blood pressure, respiratory rate, pulse rate, and body temperature measured orally (°C). The above dosing regimen is well tolerated and shows efficacy in treating asthma.
  • non-T cell-depleting, humanized, monoclonal anti-CD11a antibody should cause significantly less toxicity, sensitization, and more specific immunosuppression than currently available anti-T cell monoclonal antibodies (OKT3).
  • PK/PD pharmacokinetics and pharmacodynamics
  • Each patient receives the initial "conditioning" dose of anti-CD11a (hu 1124) at 0.5 mg/kg or 0.7 mg/kg, dependent on dose group assignment, on Day 0 at least l hour prior to surgery as summarized in Table 6 below. Thereafter, each patient receives a maintenance dose of anti-CD11a (h1124) at 0.5 mg/kg or 2.0 mg/kg each weekly visit for 11 weeks, based on the dose group.
  • Table 6 Study Design Dose Group n Group I Anti-CD 11a (hu1124) 0.5 mg/kg plus Arm A.
  • Half-dose cyclosporine 2.5-5 mg/kg
  • sirolimus prednisone 9 Arm B.
  • anti-CD11a (hu1124)
  • XOMA Sterile Water for Injection
  • anti-CD11a (hu1124) at a concentration of 100 mg/mL, 20 mmol of L-histidine, 240 mmol of ⁇ , ⁇ -trehalose, and 0.04% polysorbate 20 (pH of 6.0).
  • Vials are refrigerated at 2°C - 8°C (36°F - 46°F). Reconstituted product is stable at room temperature for up to 8 hours.
  • Safety is assessed by the incidence of adverse events, vital signs, changes in laboratory values compared with baseline (hematology, chemistry, urinalysis), infections, lymphoma, acute rejection episodes, delayed graft function, graft loss, death, incidence of human anti-humanized monoclonal antibody (HAHA).
  • the pharmacokinetic characteristics of the study drug are assessed by serial measurement of plasma concentrations of anti-CD11a (hu1124) at various time points throughout the duration of the study.
  • Flow cytometry analysis of T cells, T lymphocyte subsets (CD3/CD4/CD8), NK cells, and B lymphocytes, plus expression of CD11a on T lymphocytes are performed.
  • Gene activation in cytotoxic T lymphocytes (perforin, granzyme B, FAS L) and cytokine gene expression (IL-10, IFN gamma, IL-2, TGF beta. IL-13) in urinary lymphocytes ( Vasconcellos et al. 1998, Transplantation 66: 562-566 ) are examined.
  • the humoral immune response is studied by examining peripheral blood for anti-HLA antibody production, by ELISA.
  • the biological activity is measured as follows. Alterations in graft function are assessed by serial measurements of serum creatinine, the need for dialysis during the initial 7 days post transplant, development of proteinuria, acute rejection episodes, and response to high-dose steroid therapy (as measured by serum creatinine). As per transplant center standard of care, graft biopsies are obtained at the time of implantation, when necessary to confirm the diagnosis of acute rejection, or if rejection does not occur, 1 week after treatment completion (Day 84). Material is obtained for cytokine and cytotoxic T lymphocyte mRNA analysis, quantitation of interstitial fibrosis, and other potential markers of chronic allograft nephropathy (i.e., collagen expression).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Genetics & Genomics (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Transplantation (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP07012360A 1999-03-19 2000-03-17 Behandlung von LFA-1-assoziierten Krankheiten durch gesteigerte Dosen von LFA-1-Antagonist Withdrawn EP1854480A3 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US12535199P 1999-03-19 1999-03-19
US12522899P 1999-03-19 1999-03-19
US27304399A 1999-03-19 1999-03-19
EP00916502A EP1163003B1 (de) 1999-03-19 2000-03-17 Behandlung von lfa-1 assozieerten krankheiten durch gesteigerte dosen von lfa-1 antagonist

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
EP00916502A Division EP1163003B1 (de) 1999-03-19 2000-03-17 Behandlung von lfa-1 assozieerten krankheiten durch gesteigerte dosen von lfa-1 antagonist

Publications (2)

Publication Number Publication Date
EP1854480A2 true EP1854480A2 (de) 2007-11-14
EP1854480A3 EP1854480A3 (de) 2009-04-01

Family

ID=27383217

Family Applications (2)

Application Number Title Priority Date Filing Date
EP07012360A Withdrawn EP1854480A3 (de) 1999-03-19 2000-03-17 Behandlung von LFA-1-assoziierten Krankheiten durch gesteigerte Dosen von LFA-1-Antagonist
EP00916502A Expired - Lifetime EP1163003B1 (de) 1999-03-19 2000-03-17 Behandlung von lfa-1 assozieerten krankheiten durch gesteigerte dosen von lfa-1 antagonist

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP00916502A Expired - Lifetime EP1163003B1 (de) 1999-03-19 2000-03-17 Behandlung von lfa-1 assozieerten krankheiten durch gesteigerte dosen von lfa-1 antagonist

Country Status (11)

Country Link
US (1) US6652855B1 (de)
EP (2) EP1854480A3 (de)
JP (1) JP2002540078A (de)
AT (1) ATE439145T1 (de)
AU (1) AU764382B2 (de)
CA (1) CA2367025A1 (de)
DE (1) DE60042735D1 (de)
DK (1) DK1163003T3 (de)
ES (1) ES2331643T3 (de)
IL (2) IL145480A0 (de)
WO (1) WO2000056363A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1874821B1 (de) 2005-04-26 2013-04-17 Trion Pharma Gmbh Kombination von antikörpern mit glukokortikoiden zur behandlung von krebs
WO2009086550A1 (en) * 2008-01-03 2009-07-09 Abbott Laboratories Predicting long-term efficacy of a compound in the treatment of psoriasis
JP2012254994A (ja) * 2012-07-23 2012-12-27 Trion Pharma Gmbh 癌治療のための抗体およびグルココルチコイドの組み合わせ

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4428130A (en) 1981-05-19 1984-01-31 Nordica S.P.A. Inner boot structure particularly for ski boots
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5098833A (en) 1989-02-23 1992-03-24 Genentech, Inc. DNA sequence encoding a functional domain of a lymphocyte homing receptor
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5225538A (en) 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
US5336603A (en) 1987-10-02 1994-08-09 Genentech, Inc. CD4 adheson variants

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988006592A1 (en) 1987-02-26 1988-09-07 Dana-Farber Cancer Institute, Inc. Cloning of lfa-1
EP0289949B1 (de) 1987-05-04 1995-10-04 Dana Farber Cancer Institute Interzellulare Adhäsions-Moleküle und deren Bindungsliganden
US5002869A (en) 1987-11-02 1991-03-26 Dana-Farber Cancer Institute Monoclonal antibody specific to a novel epitope of the LFA-1 antigen of human T lymphocytes
US5071964A (en) 1988-05-04 1991-12-10 Dana-Farber Cancer Institute, Inc. Protein micelles
US5147637A (en) 1988-06-07 1992-09-15 The Rockefeller University Method of inhibiting the influx of leukocytes into organs during sepsis or other trauma
CA2008368C (en) 1989-01-24 2003-04-08 Jeffrey Greve Soluble molecule related to but distinct from icam-1
NO900155L (no) 1989-01-24 1990-07-25 Molecular Therapeutics Inc Et opploeselig molekyl som er relatert til, men forskjellig fra icam-1.
CA2050329A1 (en) 1989-03-09 1990-09-10 Timothy A. Springer Method of treating viral infections using lfa-1
CA2011633C (en) 1989-03-09 2007-05-15 Timothy A. Springer Intercellular adhesion molecule - 2 and its binding ligands
EP0432249B1 (de) 1989-06-02 1996-09-25 The Johns Hopkins University School Of Medicine Gegen die beta-kette des leukozyten-adhäsions-rezeptors gerichtete monoklonale antikörper, verfahren zu ihrer herstellung und ihre verwendung
GB9009548D0 (en) 1990-04-27 1990-06-20 Celltech Ltd Chimeric antibody and method
GB9009549D0 (en) 1990-04-27 1990-06-20 Celltech Ltd Recombinant antibody and method
WO1991018011A1 (en) 1990-05-15 1991-11-28 Swinburne Limited Inhibition of cell adhesion using intercellular adhesion molecule-1-like peptides and/or analogues thereof
CA2119128C (en) 1992-07-16 2000-05-30 Lynn M. Rose Alleviation of symptoms associated with inflammatory disease states
DE69315847T2 (de) * 1992-08-21 1998-06-25 Genentech Inc Verfahren zur behandlung einer durch lfa-1 vermittelten störung
WO1998023761A1 (en) * 1996-11-27 1998-06-04 Genentech, Inc. HUMANIZED ANTI-CD11a ANTIBODIES
US6037454A (en) * 1996-11-27 2000-03-14 Genentech, Inc. Humanized anti-CD11a antibodies

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4428130A (en) 1981-05-19 1984-01-31 Nordica S.P.A. Inner boot structure particularly for ski boots
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5336603A (en) 1987-10-02 1994-08-09 Genentech, Inc. CD4 adheson variants
US5565335A (en) 1987-10-02 1996-10-15 Genentech, Inc. Adhesion variants
US5098833A (en) 1989-02-23 1992-03-24 Genentech, Inc. DNA sequence encoding a functional domain of a lymphocyte homing receptor
US5116964A (en) 1989-02-23 1992-05-26 Genentech, Inc. Hybrid immunoglobulins
US5225538A (en) 1989-02-23 1993-07-06 Genentech, Inc. Lymphocyte homing receptor/immunoglobulin fusion proteins
US5428130A (en) 1989-02-23 1995-06-27 Genentech, Inc. Hybrid immunoglobulins
US5714147A (en) 1989-02-23 1998-02-03 Genentech Inc. Hybrid immunoglobulins

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
JONES ET AL., NATURE, vol. 321, 1986, pages 522 - 525
KOHLER; MILSTEIN, NATURE, vol. 256, 1975, pages 495
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
PRESTA, CURR. OP. STRUCT. BIOL., vol. 2, 1992, pages 593 - 596
REICHMANN ET AL., NATURE, vol. 332, 1988, pages 323 - 329

Also Published As

Publication number Publication date
JP2002540078A (ja) 2002-11-26
EP1854480A3 (de) 2009-04-01
EP1163003B1 (de) 2009-08-12
AU3759700A (en) 2000-10-09
WO2000056363A1 (en) 2000-09-28
EP1163003A1 (de) 2001-12-19
US6652855B1 (en) 2003-11-25
IL145480A0 (en) 2002-06-30
CA2367025A1 (en) 2000-09-28
IL145480A (en) 2011-04-28
ATE439145T1 (de) 2009-08-15
DE60042735D1 (de) 2009-09-24
AU764382B2 (en) 2003-08-14
DK1163003T3 (da) 2009-11-30
ES2331643T3 (es) 2010-01-12

Similar Documents

Publication Publication Date Title
EP1734997B1 (de) Natalizumab zur verwendung bei der behandlung von krankheiten mit kortikosteroid-therapie
DE69637131T2 (de) Humanisierte antikörper gegen humanes gp39, zusammensetzungen die diese enthalten und deren therapeutische verwendungen
US9512226B2 (en) Agent for treating disease
US20130059337A1 (en) Therapeutic Uses of Humanized Antibodies Against ALPHA-4 Integrin
Przepiorka et al. A phase II study of BTI-322, a monoclonal anti-CD2 antibody, for treatment of steroid-resistant acute graft-versus-host disease
JPH04316600A (ja) Ｃｄ２５結合分子
CN101367877A (zh) 人b7.1和/或b7.2特异的猴源单克隆抗体的灵长动物化形式,药用组合物
EP2260057A1 (de) Mittel zur behandlung von krankheiten
US9399679B2 (en) Therapeutic anti-TIRC7 antibodies for use in immune related and other diseases
AU7900191A (en) Humanized cdr-grafted anti-icam-1 antibodies, methods of preparation and usage thereof
CN106794255A (zh) 使用针对cd28的域抗体治疗***性红斑狼疮的方法
US7364734B2 (en) Treatment of LFA-1 associated disorders with increasing doses of LFA-1 antagonist
DE69825473T2 (de) Cd154-blockadetherapie für das syndrom der hemmung der therapeutischen proteine
US20040253237A1 (en) Methods of treatment of ulcerative colitis with anti-CD3 antibodies
US6652855B1 (en) Treatment of LFA-1 associated disorders with increasing doses of LFA-1 antagonist
Helliwell et al. Monoclonal antibodies in multiple sclerosis treatment: current and future steps
US10683359B2 (en) Anti-TNFRSF25 antibodies
TW202311293A (zh) 免疫療法之組合及其用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070711

AC Divisional application: reference to earlier application

Ref document number: 1163003

Country of ref document: EP

Kind code of ref document: P

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1110024

Country of ref document: HK

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20091102

AKX Designation fees paid

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RBV Designated contracting states (corrected)

Designated state(s): AT BE CH DE DK ES FI FR GB IE IT LI NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20130124

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1110024

Country of ref document: HK